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The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro-endocrine-immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.

This paper will update care providers on the clinical and scientific aspects of frailty which affects an increasing proportion of older people living with HIV (PLWH). The successful use of combination antiretroviral therapy has improved long-term survival in PLWH. This has increased the proportion of PLWH older than 50 to more than 50% of the HIV population. Concurrently, there has been an increase in the premature development of age-related comorbidities as well as geriatric syndromes, especially frailty, which affects an important minority of older PLWH. As the number of frail older PLWH increases, this will have an important impact on their health care delivery. Frailty negatively affects a PLWH’s clinical status, and increases their risk of adverse outcomes, impacting quality of life and health-span. The biologic constructs underlying the development of frailty integrate interrelated pathways which are affected by the process of aging and those factors which accelerate aging. The negative impact of sarcopenia in maintaining musculoskeletal integrity and thereby functional status may represent a bidirectional interaction with frailty in PLWH. Furthermore, there is a growing body of literature that frailty states may be transitional. The recognition and management of related risk factors will help to mitigate the development of frailty. The application of interdisciplinary geriatric management principles to the care of older PLWH allows reliable screening and care practices for frailty. Insight into frailty, increasingly recognized as an important marker of biologic age, will help to understand the diversity of clinical status occurring in PLWH, which therefore represents a fundamentally new and important aspect to be evaluated in their health care.

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the \"beta-amyloid hypothesis\" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the \"infection hypothesis\" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.

The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (T SCM ) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that T SCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 T SCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 T SCM . Our data thus hint that reversing T SCM defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history. Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

Extra virgin olive oil (EVOO) polyphenols are recognized for their beneficial effects on human health, yet how their concentration shapes biological outcomes remains insufficiently explored. While a daily intake of 25 mL EVOO is generally regarded as beneficial for cardiovascular protection, the high-phenolic EVOO examined in this study contains markedly higher levels of polyphenols than most EVOOs reported previously. This suggests that oils richer in polyphenols may exert distinct biological effects. To investigate this, we compared extracts from a standard EVOO and a naturally high-phenolic EVOO, along with their key phenolic compounds, hydroxytyrosol (HT) and tyrosol (Tyr). Antioxidant effects were assessed by quantifying intracellular reactive oxygen species (ROS) and lipid peroxidation. Anti-inflammatory activity was evaluated in THP-1-derived macrophages stimulated with LPS by analyzing inflammatory surface markers’ expression, cytokines’ production, and the NLRP3-inflammasome pathway. Atheroprotective potential was investigated by measuring cholesterol efflux in J774 macrophages. Both EVOO polyphenols extracts and (HT and Tyr) significantly reduced ROS and lipid peroxidation. High phenolic EVOO extract (EVOOPE+) displayed superior antioxidant activity at lower concentrations, while standard EVOO phenolic extract (EVOOPE) showed more consistent effects across doses. Both extracts favored an anti-inflammatory macrophage phenotype, as indicated by increased CD163 and IL-10 expression and reduced CD86, IFN-α, and NLRP3. Moreover, all treatments enhanced cholesterol efflux in a dose-dependent manner, with EVOOPE+ and HT producing the strongest effects. Collectively, these results highlight the capacity of EVOO polyphenols to modulate, through key bioactivity mechanisms, cardioprotective effects and emphasize the importance of polyphenols concentration in their biological efficacy.

Background Gender-related differences in humans are commonly observed in behaviour, physical activity, disease, and lifespan. However, the notion that age-related changes in the immune system differ between men and women remains controversial. To elucidate the relationship between immunological changes and lifespan, peripheral blood mononuclear cells from healthy Japanese subjects (age range: 20–90 years; N = 356) were analysed by using three-colour flow cytometry. The proliferative activities and cytokine-producing capacities of T cells in response to anti-CD3 monoclonal antibody stimulation were also assessed. Results An age-related decline in the number of T cells, certain subpopulations of T cells (including CD8 + T cells, CD4 + CDRA + T cells, and CD8 + CD28 + T cells), and B cells, and in the proliferative capacity of T cells was noted. The rate of decline in these immunological parameters, except for the number of CD8 + T cells, was greater in men than in women (p < 0.05). We observed an age-related increase or increasing trend in the number of CD4 + T cells, CD4 + CDRO + T cells, and natural killer (CD56 + CD16 + ) cells, as well as in the CD4 + T cell/CD8 + T cell ratio. The rate of increase of these immunological parameters was greater in women than in men (p < 0.05). T cell proliferation index (TCPI) was calculated from the T cell proliferative activity and the number of T cells; it showed an age-related decline that was greater in men than in women (p < 0.05). T cell immune score, which was calculated using 5 T cell parameters, also showed an age-related decline that was greater in men than in women (p < 0.05). Moreover, a trend of age-related decreases was observed in IFNγ, IL-2, IL-6, and IL-10 production, when lymphocytes were cultured with anti-CD3 monoclonal antibody stimulation. The rate of decline in IL-6 and IL-10 production was greater in men than in women (p < 0.05). Conclusion Age-related changes in various immunological parameters differ between men and women. Our findings indicate that the slower rate of decline in these immunological parameters in women than that in men is consistent with the fact that women live longer than do men.

Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently—resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the human γδ T cell family and its ligands before discussing parallels in mice. By covering the ontogeny and homeostasis of γδ T cells during their lifespan, we will better capture their evolution and responses to age-related stressors. Finally, we will identify knowledge gaps within these topics that can advance our understanding of the relationship between γδ T cells and aging, as well as age-related diseases such as cancer.

Food scientists have studied the many health benefits of polyphenols against pernicious human diseases. Evidence from scientific studies has shown that earlier healthy lifestyle changes, particularly in nutrition patterns, can reduce the burden of age-related diseases. In this context, a large number of plant-derived components belonging to the class of polyphenols have been reported to possess neuroprotective benefits. In this review, we examined studies on the effect of dietary polyphenols, notably from Punica granatum L., on neurodegenerative disease, including Alzheimer’s disease, which is symptomatically characterized by impairment of cognitive functions. Clinical trials are in favor of the role of some polyphenols in maintaining neuronal homeostasis and attenuating clinical presentations of the disease. However, discrepancies in study design often bring inconsistent findings on the same component and display differences in their effectiveness due to interindividual variability, bioavailability in the body after administration, molecular structures, cross-blood-brain barrier, and signaling pathways such as nuclear factor kappa B (NF-κB). Based on preclinical and clinical trials, it appears that pomegranate may prove valuable in treating neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Therefore, due to the lack of information on human clinical trials, future in-depth studies, focusing on human beings, of several bioactive components of pomegranate’s polyphenols and their synergic effects should be carried out to evaluate their curative treatment.